An Update on Existing and Emerging Data for Meropenem-Vaborbactam

Clinical Therapeutics/Volume xxx, Number xxx, xxxx

An Update on Existing and Emerging Data for Meropenem-Vaborbactam Bethany R. Shoulders, PharmD, BCCCP; Anthony M. Casapao, PharmD, MPH; and Veena Venugopalan, PharmD, BCIDP Department of Pharmacotherapy and Translational Research, University of Florida College of Pharmacy, Gainesville, FL, USA ABSTRACT Purpose: The search for new agents to treat multidrug-resistant gram-negative bacterial infections has been ongoing. Specifically, carbapenem-resistant Enterobacteriaceae (CRE) infections often exhibit multiple resistance mechanisms, including alterations in drug structure, bacterial efflux pumps, and drug permeability. Vaborbactam, a cyclic boronic acid pharmacophore, has the highest potency in vitro with meropenem as an inhibitor of class A carbapenemases, including Klebsiella pneumoniae carbapenemase (KPC). This combination product was approved by the US Food and Drug Administration for complicated urinary tract infections (cUTIs) in August 2017, and recent Phase III trial data have expanded the literature available. This article aimed to describe the literature regarding spectrum of activity, dosing and administration, including pharmacokinetic and pharmacodynamics properties, safety profile, and efficacy end points. Methods: The terms meropenem, vaborbactam, RPX7009, and meropenem-vaborbactam were used to search for literature via PubMed, ClinicalTrials. gov, and published abstracts from 2013 to July 2019. Abstracts from IDWeek 2019 were also searched via these terms. Results were limited to availability in English. Findings: Meropenem-vaborbactam covers a spectrum of gram-negative bacterial pathogens, including K pneumoniae, Escherichia coli, and Enterobacter cloacae complex. Although the addition of vaborbactam to meropenem results in MIC lowering for KPC-positive Enterobacteriaceae, in vitro data reveal limited activity against resistant strains of Acinetobacter species and Pseudomonas aeruginosa. Data from 2 Phase III studies compare

the drug with available therapies for the following indications: cUTIs, acute pyelonephritis, hospitalacquired and ventilator-acquired bacterial pneumonia, bacteremia, and complicated intraabdominal infections. Outcomes include an improvement in clinical success when compared with piperacillin-tazobactam (98.4% vs 94%; 95% CI, 0.7%e9.1%; P < 0.001 for noninferiority) for overall treatment of cUTIs and acute pyelonephritis and clinical cure (64.3% vs 33.3%; P ¼ 0.04) when compared with best available therapy for CRE infections in various sites of infection. Adverse events have been described as mild to moderate, with few events requiring discontinuation of the drug therapy. Implications: Currently, meropenem-vaborbactam is approved for treatment of cUTIs and acute pyelonephritis; however, off-label use, in particular for CRE infections, appears beneficial. Clinical trials to date have found an improvement in clinical cure and potentially an improved tolerability compared with standard therapies. Most of the evidence for meropenem-vaborbactam activity and the role in therapy focuses on KPC-producing organisms; however, because in vitro activity has been found with some noneKPC-producing CRE, its role may be further described from upcoming in vivo cases and postmarketing research. (Clin Ther. 2020; XX:XXXeXXX) © 2020 Elsevier HS Journals, Inc. (Clin Ther. xxxx;xxx:xxx) © 2020 Elsevier Inc. Key words: carbapenemase-producing organisms, Klebsiella pneumonia carbapenemase, meropenem-

Accepted for publication January 29, 2020 https://doi.org/10.1016/j.clinthera.2020.01.023 0149-2918/$ - see front matter © 2020 Elsevier Inc.

▪▪▪ xxxx

1

Clinical Therapeutics vaborbactam, multidrug-resistant gram-negative organisms, vaborbactam.

previous European Congress of Clinical Microbiology and Infectious Diseases and IDWeek 2019 were reviewed.

INTRODUCTION

RESULTS Chemical Structures and Pharmacodynamics

Multidrug resistant organisms (MDROs) are the third leading cause of death in the United States, accounting for >70,000 inpatient and >90,000 outpatient deaths.1 The Centers for Disease Control and Prevention published a report in 2013 that recognized urgent and serious pathogens and outlined actions to combat this threat, including but not limited to the development and judicious use of new agents.2 Meropenem-vaborbactam, a new antimicrobial agent approved by the US Food and Drug Administration (FDA) in 2017, contains a cyclic boronic acid pharmacophore that expands its spectrum of activity to cover some of the gramnegative MDROs. Meropenem has generally been able to maintain activity against resistant gram-negative organisms, such as extended-spectrum b-lactamase (ESBL) Enterobacteriaceae, multidrug-resistant Pseudomonas aeruginosa, and AmpC b-lactamase producers; however, the spread of carbapenemases has limited meropenem's use. Further steps to protect meropenem's integrity and activity are needed. Carbapenemases are divided into 4 classes: A, B, C, and D. Vaborbactam inhibits class A carbapenemases, such as Klebsiella pneumoniae carbapenemase (KPC).3 Meropenem-vaborbactam, although currently FDA approved only for use in complicated urinary tract infections (cUTIs), has reported effectiveness in Phase III trials to cover other infectious sources and has become a favorable treatment option for carbapenem-resistant Enterobacteriaceae (CRE) infections. As a last line of defense against MDROs, it is imperative to understand and review its spectrum of activity, dosing and administration, as well as tolerability and efficacy data.

MATERIALS AND METHODS Searches of PubMed and ClinicalTrials.gov were conducted for articles published from 2013 to July 2019 that were available in English using the terms meropenem, vaborbactam, RPX7009, and meropenem-vaborbactam. In addition, abstracts from

2

Meropenem-vaborbactam is a carbapenem with a blactamase inhibitor combination antibiotic. Its chemical structures are shown in Figure. Meropenem, a carbapenem antibiotic, is generally bactericidal against most susceptible organisms.4e7 Meropenem penetrates the outer membrane of cell walls and inhibits the third and final stage of bacterial cell wall synthesis. It binds to several penicillin-binding proteins (PBPs), depending on the organism. For example, meropenem binds to PBP-2, PBP-3, and PBP-4 for Escherichia coli and P aeruginosa, Whereas meropenem binds to PBP-1, PBP-2, and PBP-4 of Staphylococcus aureus.8 Meropenem has a higher affinity for PBP-1a, PBP-1b, and PBP-2 compared with its ability to bind to PBP-3.9 Meropenem has activity against organisms that produce ESBL.10 Meropenem's structure includes the signature 5-membered carbon ring fused to a blactam ring with a methyl group at C4 that improves its safety profile with less epileptogenic potential, and its structure at C3 allows for its affinity to different PBPs. Vaborbactam is a noneb-lactam, cyclic boronic acid highly efficient at hydrolyzing serine blactamases.11 The covalent adduct that forms between active site serine of b-lactamases and the boronate moiety mimics the tetrahedral transition state in the acylation or diacylation reaction pathway, resulting in rapid enzymatic inactivation.11 Boronic acids are effective against serine b-lactamases because the electron-deficient boron atom acts as a strong electrophile with a high propensity to form reversible covalent bonds with catalytic serine blactamases.12 Vaborbactam is a highly efficient inhibitor because as a noneb-lactam it is not hydrolyzed by b-lactamases to a significant degree and binding to b-lactamases is reversible. The reversible nature of the enzymeeinhibitor complex means that the inhibitor is not hydrolyzed but recycled after the diacylation process, regenerating molecules capable of interacting with free enzyme.13 Vaborbactam has a thiophene moiety, similar to that

Volume xxx Number xxx

B.R. Shoulders et al.

Figure.

Clinical structures of meropenem (left) and vaborbactam (right).

in cephalothin and cefoxitin, which enhances its activity against KPC enzymes.14,15

Pharmacokinetic Properties Meropenem-vaborbactam is administered only as an intravenous agent. Protein binding is considered very low for meropenem (approximately 2%) and relatively low to medium for vaborbactam (33%). Volumes of distribution are proportionally similar for both meropenem (20.2 L) and vaborbactam (18.6 L).7,14 Meropenem goes through the minor pathway for elimination by hydrolysis of the blactam ring; however, vaborbactam does not go through any metabolic pathway.6,7 Both compounds are primarily excreted through the kidneys (40%e 60% of meropenem and 75%e95% of vaborbactam in the urine as unchanged drugs). In addition, 22% of meropenem does become hydrolyzed and inactive after 24e48 h. A small percentage of meropenem (2%) is eliminated fecally. The half-life of meropenem is 1.22 h, whereas the half-life of vaborbactam is 1.68 h. Meropenem is a substrate of the organic anion transporter (OATs) 1 and 3 in the proximal tubule of the kidney. Vaborbactam does not inhibit any hepatic or renal transportation and is not a substrate of any isoenzymes or transporters.6,7 Compared with other b-lactamase inhibitors, vaborbactam exhibits a much higher percentage of protein binding; however, it has a lower volume of distribution. The volume of distribution at steady state for meropenem and vaborbactam is similar. In an lung epithelial lining fluid study, when unbound plasma concentrations were considered, epithelial lining fluid penetration of meropenem and vaborbactam was 65% and 79%, respectively, indicating a similar exposure.16 See Table I for the pharmacokinetic comparisons of meropenem,

▪▪▪ xxxx

vaborbactam, ceftazidime, avibactam, imipenem, and relebactam.6,7,17e20 The fixed-dose combination of meropenemvaborbactam is 1:1 carbapenem and b-lactamase inhibitor, which is different from ceftazidimeavibactam (4:1) and imipenem-cilastatin-relebactam (5:1).6,7,17e20 Meropenem and vaborbactam have linear pharmacokinetic properties. The pharmacokinetic profiles of the individual drugs are similar to those with the combination (even in renal impairment), which may potentially contribute to the increased stability against enzymatic degradation.21

Dosing and Administration The dosing and administration considerations of this combination medication are also related to optimizing activity against resistant organisms. Phase I and Phase III models used doses of 1e2 g of meropenem and 250 mg to 2 g of vaborbactam, each administered every 8 h by a 3-h infusion. The highdose extended infusion strategy of meropenemvaborbactam, optimizes the pharmacokinetic and pharmacodynamic properties of the drug. In a hollow fiber model, the 2-g and 2-g combination correlated with 24-h free vaborbactam AUC of approximately 550, and this pharmacodynamic model reported bactericidal activity with meropenem-vaborbactam MICs up to 16 mg/mL.22 Therefore, the FDAapproved total dose with normal renal function is 4 g (2 g of meropenem and 2 g of vaborbactam) as a 3-h IV infusion every 8 h with a reduction to 2 g (1 g of meropenem and 1 g of vaborbactam) every 8 h for an estimated glomerular filtration rate of 30e49 mL/ min and a reduction in frequency to every 12 h for an estimated glomerular filtration rate of 15e29 mL/ min. Dosing for an estimated glomerular filtration rate <15 mL/min and hemodialysis is 1 g (0.5 g of

3

Clinical Therapeutics

Table I.

Comparison of pharmacokinetic properties for new b-lactam and b-lactamase inhibitor combination antimicrobials.

Antibiotic

Protein Binding, %

Meropenem6

Approximately 2

Vaborbactam7

Volume of Distribution, L

Renal Excretion, % Unchanged

Half-Life, h

Miscellaneous Kinetics

20.2

40e60

1.22

33

18.6

75e95

1.68

Hydrolysis of b-lactam ring and 22% becomes inactive after 24e48 h; substrate of OAT1 and OAT3 renal transporters Not a substrate or an inhibitor of transportation

Ceftazidime17 Avibactam18

10 5e8

13.6 22

90 85

1.5e2 2

Imipenem19

20

24.3

63

1

Relebactam20

22

19

90

1.2

Substrate for OAT1 and OAT3 renal transporters; clearance decreases with renal dysfunction Metabolized in the renal proximal tubule Renal clearance is greater than GFR; substrate for PAT3, OAT4, MATE1, and MATE2K transporters

GFR ¼ glomerular filtration rate; MATE ¼ multidrug and toxin extrusion; OAT ¼ organic anion transporter.

meropenem and 0.5 g of vaborbactam) IV every 12 h with a dose administered after dialysis if applicable.7 Vaborbactam exposure is specifically greater when administered after hemodialysis. Patients with MDROs are often critically ill and require continuous renal replacement therapy. Continuous veno-venous hemofiltration clears meropenem to a greater extent than vaborbactam.23 Recommended dosing frequency for meropenem in continuous renal replacement therapy is every 8e12 h with a range of 1e4 g/d, depending on mode of continuous renal replacement therapy, and a recent trial concluded that extrapolating existing data for meropenem to meropenem-vaborbactam is appropriate, citing

4

doses of 1e2 g every 8 h for effluent flow rates of 1e4 L/h.24,25 The medication is provided as a dry powder in a singl-dose vial that requires reconstitution with 0.9% sodium chloride and diluted to final volumes of approximately 100e1000 mL of 0.9% sodium chloride, depending on the number of vials needed per dose.7 Furthermore, with the approved administration during 3 h, y-site compatibility has been studied and found to be compatible with 73 of 88 medications, although the solution can only be mixed with 0.9% sodium chloride. Although incompatibilities were infrequent, example of medications with physical incompatibilities included

Volume xxx Number xxx

B.R. Shoulders et al. albumin, amiodarone, calcium chloride, and antimicrobials, such as daptomycin and ceftaroline.26

Drug Interactions Significant drug interactions include coadministration with valproic acid and probenecid, which interact with the meropenem component. The major drug interaction with valproic acid has been described in the literature as a significant decrease in valproic acid serum levels, resulting in increased risk of seizure activity.7,27 Increased dosing of valproic acid does not consistently result in therapeutic levels; therefore. Coadministration should be avoided.27 Coadministration of meropenem with probenecid results in a significant increase in meropenem exposure and half-life because probenecid inhibits the renal tubular secretion of the medication as meropenem is a substrate of OAT1 and OAT3.6 No significant drug interactions unique to the combination product have been reported at this time.

Spectrum of Activity Meropenem-vaborbactam covers a wide spectrum of gram-negative organisms. The cyclic boronic acid pharmacophore vaborbactam remains active despite the presence of class A (KPC, CTX-M, SHV, and TEM) and class C (P99, MIR, and FOX) blactamases.28 Because of vaborbactam's high affinity for KPC and meropenem's ability to overcome ESBLs and cephalosporinases, the meropenemvaborbactam combination is able to maintain its susceptibility to many organisms in the Enterobacteriaceae family, including Enterobacter cloacae, E coli, and K pneumoniae. A proposed mechanism for vaborbactam's enhanced activity against KPC is the low off-rate time, which produces greater enzyme residence time.29 Wilson et al30 found that clinical isolates harboring wildtype or mutant blakpc had 100% activity to meropenem-vaborbactam. In addition, those blaKPC isolates with reduced susceptibility to ceftazidimeavibactam retained activity to meropenemvaborbactam.30 Vaborbactam may not be able to lower MICs for meropenem as effectively against Acinetobacter baumanii, P aeruginosa, and Stenotrophomonas maltophilia, and its consistent activity has not been established yet in clinical trials.29,31,32 Recent data describe the discordance

▪▪▪ xxxx

between meropenem and meropenem-vaborbactam against P aeruginosa. Patel et al33 evaluated close to 3000 clinical isolates of P aeruginosa and found discordance (meropenem-resistant and meropenemvaborbactam susceptible) by at least 1 to 3 MIC doubling dilutions for 459 isolates (15%). Fifty-nine isolates (2%) had meropenem-vaborbactam MIC reduction by  3 doubling dilutions. The mechanisms of resistance that produce this discordance in susceptibility have yet to be elucidated.33 There is no added benefit with meropenem combined with vaborbactam on grampositive or anaerobic activity.7 See Table II for a comparison of meropenem and meropenemvaborbactam in regard to mechanisms of resistance and the correlating MDRO activity. Vaborbactam has variable activity against class B metalloeb-lactamases (IMP, NDM, and VIM) and limited activity against class D carbapenemases (OXA-48 and its variants). Mutations in both porin genes, ompK35 and ompK36, are required to reduce susceptibility to carbapenems.30 OmpK36, which has a smaller channel than OmpK35, appears to play a more significant role in the passage of vaborbactam across the outer membrane than OmpK35.29 An in vitro study30 found that clinical KPC-producing K pneumoniae isolates harboring OmpK36 have higher MICs (approximately 8-fold) but remain susceptible to meropenem-vaborbactam. A study conducted by Yasmin et al34 performed whole genome sequencing on 105 K pneumoniae isolates with whole and partial mutations in OmpK35 and OmpK36. Eleven of 107 isolates (10.4%) were resistant to meropenem-vaborbactam. Notably, only one resistant isolate harbored a gene for metalloeb-lactamase production. Porin channel variants due to gene mutations in OmpK35 and Ompk36 were identified as the underlying mechanisms for meropenem-vaborbactam resistance. The major expressed efflux pump, AcrAB, reduces carbapenem susceptibility in clinical isolates of Enterobacteriaceae. Vaborbactam susceptibilities are unaffected by the presence of AcrAB efflux pumps.29 In regard to the variable activity against class B metallodb-lactamases, a recent in vitro study35,36 found that vaborbactam has activity against IMP-1 more than VIM-1 more than VIM-2 more than NDM-1, which may indicate additional in vivo activity of vaborbactam or favor this b-lactamase

5

Clinical Therapeutics

Table II.

Comparison of meropenem an meropenem-vaborbactam: mechanisms of b-lactamase resistance and activity.13,46e49

Ambler Molecular Classification

Enzyme(s)

b-Lactamase

Enterobacter species, Escherichia coli, and Klebsiella species Metalloeb-lactamases Enterobacter species, E. coli, and Klebsiella species Cephalosporinases Acinetobacter species, Citrobacter species, Enterobacter species, Providencia species, Pseudomonas species, and Serratia species Oxacillinases Acinetobacter species and Pseudomonas species

Meropenem MeropenemActivity vaborbactam Activity

A

TEM, SHV, Penicillinases CTX-M, and KPC

Variable

Yes

B

IMP, VIM, and NDM

No

No

C

AmpC

Yes

Yes

D

OXA

Variable

Variable

inhibitor in future drug development. The combination of aztreonam with b-lactam and b-lactamase combinations has activity against Enterobacteriaceae coproducing NDM and serine blactamases. A time-kill analysis was performed by Biagi et al37 on 8 clinical Enterobacteriaceae isolates coproducing NDM and at least 1 serine b-lactamase. All isolates were resistant to meropenemvaborbactam, and all but 1 were resistant to aztreonam. Aztreonam combined with meropenemvaborbactam was synergistic against all aztreonam resistant strains (7 of 8), except for an OXA-232 producing K pneumoniae strain.37 The noneb-lactamebased b-lactamase inhibitors relebactam and vaborbactam combined with imipenem or meropenem, respectively, in commercially available products also have in vitro activity against Mycobacterium abscessus complex infections. These b-lactamase inhibitors exhibited lower MICs for most carbapenems and cephalosporins, including meropenem. This pharmacodynamic improvement may allow meropenem-vaborbactam to become a preferred agent for M abscessus complex lung infections as well.38

6

Common Representative Organism(s)

Clinical Studies The tolerability and efficacy of meropenemvaborbactam were evaluated in 2 Phase III studies. Targeting Antibiotic Nonsusceptible Gram-Negative Organisms (TANGO) I was a Phase III, multicenter, randomized trial that compared meropenemvaborbactam (2 g/2 g during 3 h) with piperacillintazobactam (4 g/0.5 g during 30 min) in adults with cUTIs, including pyelonephritis. Patients received meropenem-vaborbactam or piperacillin-tazobactam for a total of 10 days.39 The primary efficacy end point was assessed using the FDA and European Medicines Agency (EMA) criteria. A total of 550 adults with cUTIs were randomized to treatment groups. Of the randomized patients, 545 received at least 1 dose of the study drugs (272 received meropenem-vaborbactam and 273 received piperacillin-tazobactam), and 374 (68%) comprised the microbiologically modified intent-to-treat population. Baseline demographic characteristics between the treatment groups were similar, with comparable incidence of pyelonephritis between the groups. The most common urinary pathogens in the trial were E coli and K pneumoniae. Resistance among the isolated urinary pathogens to meropenem

Volume xxx Number xxx

B.R. Shoulders et al. was low (1%). However, 15% of isolates were resistant to piperacillin-tazobactam. Noninferiority was met for the FDA and EMA primary end points. For the FDA primary end point, at the end of treatment, the overall success rate in the microbiologically modified intent-to-treat population was 98% with meropenem-vaborbactam versus 94% with piperacillin-tazobactam. For the EMA primary end point, microbial eradication in the microbiologically modified intent-to-treat population occurred in 67% of the meropenem-vaborbactam arm versus 58% in the piperacillin-tazobactam arm (P < 0.001 for noninferiority). In the meropenemvaborbactam and piperacillin-tazobactam groups, the incidence of adverse events were similar. TANGO II was a Phase III, randomized, prospective, multicenter, multinational, open-label, active-controlled trial of adults with infections due to confirmed or suspected CRE.40 TANGO II was conducted to evaluate the efficacy and tolerability of meropenem-vaborbactam monotherapy versus best available therapy (BAT) in adults with serious infections due to CRE. The study included adult patients with cUTIs or acute pyelonephritis, hospitalacquired or ventilator-associated bacterial pneumonia, bacteremia or complicated intraabdominal infection, and confirmed or suspected (evidence in culture or molecular testing within past 90 days) CRE pathogen, requiring 7 days of intravenous therapy. Patients randomized to meropenem-vaborbactam received 7e14 days of treatment as monotherapy (2 g/2 g) via intravenous infusion for 3 h every 8 h. BAT was selected by the primary service and confirmed by the study investigators. Efficacy end points assessed included clinical cure and microbiological cure at the end of treatment and at test of cure (which is a mean [SD] of 7 [2] days after end of treatment) in the microbiological CREemodified intention-to-treat (mCRE-MITT) population. The mCRE-MITT was defined as patients who received at least 1 dose of the study drug and had a pathogen confirmed as CRE. In addition, day 28 all-cause mortality was evaluated in this population. Seventy-seven patients were randomized to either treatment group, with 75 patients receiving at least 1 dose of the study drug (50 meropenem-vaborbactam and 19 BAT). The most common types of infection in the MITT population were bacteremia (36%) and

▪▪▪ xxxx

cUTI (45%). When baseline characteristics were compared, more patients in the meropenemvaborbactam arm had prior antibiotic failure (20% vs 0%) and systemic inflammatory response syndrome (44% vs 40%). The most frequent baseline pathogen was K pneumoniae (58.7%). The meropenem MIC50 for KPC-producing K pneumoniae was 64 mg/mL in both groups. Five K pneumoniae isolates had a meropenem-vaborbactam MIC >4 mg/mL (3 patients randomized to meropenem-vaborbactam and 2 to BAT). Metalloeblactamases or class D carbapenemases (NDM or OXA-48) were detected in 4 isolates and 1 produced KPC-3 (randomized to BAT). The BAT arm comprised a number of treatment regimens. Most patients received combination therapy that included a carbapenem, polymyxin, or aminoglycoside. Sixty percent of patients received at least 1 antimicrobial agent that had in vitro susceptibility based on Clinical Laboratory Standards Institute breakpoints. In the mCRE-MITT population, meropenemvaborbactam was associated with higher rates of clinical cure compared with BAT at end of treatment (66% vs 33%; P ¼ 0.03) and test of cure (59% vs 27%; P ¼ 0.02). Microbiological cure rates were also greater with meropenem-vaborbactam (66% vs 40%; P ¼ 0.09). Day 28 all-cause mortality was less frequent with meropenem-vaborbactam than BAT (16% vs 33%; P ¼ 0.20). A post hoc analysis of the TANGO II trial was recently conducted to evaluate the efficacy of meropenem-vaborbactam versus BAT in the subgroup of patient without prior antimicrobial failure.41 Patients without prior antibiotic failure belonging to the mCRE-MITT population were divided into 2 study groups: (1) those who received meropenem-vaborbactam monotherapy as first-line therapy and (2) those who received BAT as first-line therapy. The study results revealed that meropenem-vaborbactam was associated with a 43% absolute increase in clinical cure rate at test of cure compared with BAT (95% CI, 13.7e72.1).

Postmarketing Experience Clinical data evaluating the use of meropenemvaborbactam in the clinical setting are emerging. Shields et al42 describe the use of meropenemvaborbactam in 19 patients with KPC-producing CRE at a large academic facility. The most common

7

Clinical Therapeutics infection type was bacteremia (7 of 19 patients [37%]). Sixty-eight percent of patients were in the intensive care unit, and the median (interquartile range) Acute Physiology, Age and Chronic Health Evaluation II and Sequential Organ Failure Assessment (SOFA) scores were 18 (7e40) and 4 (1e13), respectively. All isolates in this cohort were susceptible to meropenem-vaborbactam. Success with treatment was achieved in 63%, and survival at 30 days was 89%. Microbiological failure occurred in 32% of patients. One patient developed an intra-abdominal infection due to a meropenem-vaborbactam nonsusceptible KPC-3 isolate after 12 days of treatment. Although decreased in vitro susceptibility to meropenem-vaborbactam due to porin-related gene mutations in OmpK35 and Ompk36 has been described in carbapenem-resistant K pneumoniae isolates, reports of emergence of drug resistance after meropenem-vaborbactam treatment in the clinical setting is uncommon.43 Ackley et al44 conducted a multicenter, retrospective study of adults with CRE infections who received ceftazidime-avibactam or meropenem-vaborbactam for >72 h. The objective of the study was to compare clinical outcomes, including recurrence of infection and emergence of drug resistance, in patients who received ceftazidimeavibactam versus meropenem-vaborbactam for CRE infections. A total of 64 (61%) of 105 patients received ceftazidime-avibactam in combination with another antimicrobial agent (most frequently colistin). A total of 22 of 26 patients in the meropenemvaborbactam arm received monotherapy. Clinical success was achieved in 62% of patients taking ceftazidime-avibactam compared with 69% of patients taking meropenem-vaborbactam. Rates of recurrent CRE infection were greater in the meropenem-vaborbactam group (19%) compared with the ceftazidime-avibactam group (14%); however, this difference was not statistically significant. A key finding in the post hoc subgroup analysis of patients with recurrent CRE infection was that ceftazidime-avibactam monotherapy was associated with MIC increases in 5 isolates (22%) compared with 1 isolate in the ceftazidime-avibactam combination group and none in the meropenemvaborbactam group.

8

Safety Profile Adverse reactions were compared with piperacillintazobactam in the TANGO I trial, with headache, phlebitis or infusion site reactions, and diarrhea cited as the most common symptoms.39 When compared with BAT in the TANGO II trial, meropenemvaborbactam was associated with fewer adverse events and nephrotoxicity. Of the 42 adverse events identified in the study, 22 (52.4%) were mild to moderate, and diarrhea, anemia, and hypokalemia were reported at a >10% prevalence.40 In the event of overexposure of the drug, meropenemvaborbactam was dialyzable, with 38% and 53% removed in dialysate after an intermittent hemodialysis session.7 A randomized controlled trial of the effects of meropenem-vaborbactam on QT/ QTc intervals in healthy volunteers was completed in November 2018 without published results.45 There is an insufficient amount of safety profile data for use in pregnant and breastfeeding women.

DISCUSSION Meropenem-vaborbactam is a combination antimicrobial agent that has a chemical structure that allows for an enhanced activity against KPCproducing strains of Enterobacteriaceae. It has been approved for administration as a 2-g/2-g combination intravenous product during 3 h for cUTIs but also has Phase III clinical trial data for tolerability and efficacy in pneumonia, complicated intraabdominal infections, and bacteremia. Meropenemvaborbactam's niche has yet to be established, but it has been efficacious as monotherapy in vivo against these specific carbapenem-resistant organisms with KPC resistance in various infections. Postmarketing published data have been limited to case reports in which it has been effective in the setting of the development of ceftazidime-avibactameresistant isolates.46e48 In vitro data indicate a possible role in M abscessus complex infections and non-KPC resistance with other class A and C b-lactamases.38 To date, few reports of resistance with meropenemvaborbactam are available; however, judicious use through restrictive utilization policies at institutions should be encouraged.

Volume xxx Number xxx

B.R. Shoulders et al.

CONCLUSION Meropenem-vaborbactam is tolerable and efficacious among MDROs and in combination with other new agents will help to prevent an era in which antibiotics are no longer effective. Additional studies related to its use beyond Phase III clinical trials are needed to fully understand and outline dosing strategies, preferences over other similar agents, and long-term clinical cure outcomes.

ACKNOWLEDGMENTS Each author contributed to the methods of the review. Bethany R. Shoulders compiled literature and references and coordinated evaluation among the authors. Each author contributed to initial drafting and revisions and approved the final manuscript.

REFERENCES 1. Burnham JP, Olsen MA, Kollef MH. Re-estimating annual deaths due to multidrug-resistant organisms infections. Infect Control Hospit Epidemiol. 2019;40:112e113. 2. U.S. Department of Health and Human Services Centers for Disease Control and Prevention. Antibiotic resistance threats in the United States, 2019. Available at: https:// www.cdc.gov/drugresistance/pdf/threats-report/2019-arthreats-report-508.pdf. Accessed January 17, 2020. 3. Queenan AM, Bush K. Carbapenemases: the versatile blactamases. Clin Microbiol Rev. 2007;20:440e458. 4. Inderlied CB, Lancero MG, Young LS. Bacteriostatic and bactericidal in-vitro activity of meropenem against clinical isolates, including Mycobacterium avium complex. J Antimicrob Chemother. 1989;24(Suppl A):85e99. 5. King A, Boothman C, Phillips I. Comparative in-vitro activity of meropenem on clinical isolates from the United Kingdom. J Antimicrob Chemother. 1989;24(Suppl A):31e45. 6. Merrem (Meropenem for Injection) Package Insert. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2019 Apr. 7. Vabomere (Meropenem; Vaborbactam) Package Insert. Parsippany, NJ: The Medicines Company; 2018 Jul. 8. Baldwin CM, Lyseng-Williamson KA, Keam SJ. Meropenem: a review of its use in the treatment of serious bacterial infections. Drugs. 2008;68:803e838. 9. Zhanel GC, Wiebe R, Dilay L. Comparative review of the carbapenems. Drugs. 2007;67:1027e1052. 10. Guiterrez-Gutierrez B, Bonomo RA, Carmeli Y, et al. Ertapenem for the treatment of bloodstream infections due to ESBL-producing Enterobacteriaceae: a multinational pre-registered cohort study. J Antimicrob Chemother. 2016;71:1672e1680.

▪▪▪ xxxx

11. Hecker SJ, Reddy KR, Totrov M, et al. Discovery of cyclic boronic acid b-lactamase inhibitor (RPX7009) with utility vs class A Serine Carbapenemases. J Med Chem. 2015;58: 3682e3692. 12. Livermore DM, Mushtaq S. Activity of biapenem (RPX2003) combined with the boronate b-Lactamase Inhibitor RPX7009 against carbapenem-resistant Enterobacteriaceae. J Antimicrob Chemother. 2013;68:1825e1831. 13. Crass RL, Pai MP. Pharmacokinetics and pharmacodynamics of b-lactamase inhibitors. Pharmacotherapy. 2019;39:182e195. 14. Jorgensen S, Rybak MJ. Meropenem and vaborbactam: stepping up the battle against carbapenem-resistant Enterobacteriaceae. Pharmacotherapy. 2018;38: 444e461. 15. Morandi S, Morandi F, Caselli E, et al. Structure-based optimization of cephalothin-analogue boronic acids as blactamase inhibitors. Bioorg Med Chem. 2008;16:1195e1205. 16. Wenzler E, Gotfried MH, Loutit JS, et al. MeropenemRPX7009 concentrations in plasma, epithelial lining fluid, and alveolar macrophages of healthy adult subjects. Antimicrob Agents Chemother. 2015;59:7232e7239. 17. Fortaz (Ceftazidime for Injection Single Vials) Package Insert. Research Triangle Park, NC: GlaxoSmithKline LLC; 2017 Jul. 18. Avycaz (Ceftazidime and Avibactam for Injection) Package Insert. Irvine, CA: Allergan USA, Inc.; 2019 Mar. 19. Primaxin (Imipenem and Cilastatin Solution for Injection) Package Insert. Whitehouse Station, NJ: Merck & Co, Inc.; 2018 Dec. 20. Recarbrio (Imipenem; Cilastatin; Relebactam) Package Insert. Whitehouse Station, NJ: Merck & Co, Inc.; 2019 July. 21. Rubino CM, Bhavnani SM, Loutit JS, et al. Phase 1 study of the safety, tolerability, and pharmacokinetics of vaborbactam and meropenem alone and in combination following single and multiple doses in healthy adult subjects. Antimicrob Agents Chemother. 2018;62. e02228e302217. 22. Sabet M, Tarazi Z, Rubio-Aparicio D, et al. Activity of simulated human dosage regimens of meropenem and vaborbactam against carbapenem-resistant Enterobacteriaceae in an in vitro hollow-fiber model. Antimicrob Agents Chemother. 2018;62. e01969ee01917. 23. Pandey S, Wallis S, Sime FB, et al. Ex Vivo Characterization of Effects of Renal Replacement Therapy Modalities and Settings on Pharmacokinetics of Meropenem-Vaborbactam. Madrid, Spain: European Congress of Clinical Microbiology and Infectious Diseases (ECCMID); April 21-24, 2018. 24. Heintz BH, Matzke GR, Dager WE. Antimicrobial dosing concepts and recommendations for critically ill adult patients receiving continuous renal replacement therapy or intermittent hemodialysis. Pharmacotherapy. 2009;29: 562e577.

9

Clinical Therapeutics 25. Sime FB, Pandey S, Karamujic N, et al. Ex vivo characterization of effects of renal replacement therapy modalities and settings on pharmacokinetics of meropenem and vaborbactam. Antimicrob Agents Chemother. 2018;62:e01306 ee01318. 26. Kidd JM, Avery LM, Asempa TE, Nicolau DP, Kuti JL. Physical compatibility of meropenem and vaborbactam with select intravenous drugs during simulated y-site administration. Clin Ther. 2018;40: 261e269. 27. Coves-Orts FJ, Borras-Blasco J, Navarro-Ruiz A, et al. Acute seizures due to a probable interaction between valproic acid and meropenem. Ann Pharmacother. 2005;39:533e537. 28. Castanheira M, Rhomberg PR, Flamm RK, Jones RN. Effect of the blactamase inhibitor vaborbactam combined with meropenem against serine carbapenemase-producing Enterobacteriaceae. Antimicrob Agents Chemother. 2016;60:5454e5458. 29. Lomovskaya O, Sun D, RubioAparicio D, et al. Vaborbactam: spectrum of beta-lactamase inhibition and impact of resistance mechanisms on activity in Enterobacteriaceae. Antimicrob Agents Chemother. 2017;6, e01443-17. 30. Wilson WR, Kline EG, Jones CE, et al. Effects of KPC variant and porin genotype on the in vitro activity of meropenem-vaborbactam against carbapenem-resistant Enterobacteriaceae. Antimicrob Agents Chemother. 2019;63, e02048-18. 31. Domenech-Sanchez A, HernandezAlles S, Martinez-Martinez L, Benvedi VJ, Alberti S, et al. Identification and characterization of a new porin gene of Klebsiella pneumoniae: its role in beta-lactam antibiotic resistance. J Bacteriol. 1999;181:2726e2732. 32. Jean SS, Lee WS, Lam C, Hsu CW, Chen RJ, Hsueh PR, et al. Carbapenemase-producing Gram-

10

33.

34.

35.

36.

37.

38.

39.

negative bacteria: current epidemics, antimicrobial susceptibility and treatment options. Future Microbiol. 2015;10:407e425. Patel TS, Kaye KS, Krishnan J, et al. Comparative in vitro activity of meropenem/vaborbactam and meropenem against a collection of real-world clinical isolates of Pseudomonas aeruginosa. In: Poster Presented at: ID Week. 2019 Oct 2e6 [Washington, DC]. Yasmin M, Marshall SH, Jacobs M, et al. Meropenem (MV) in vitro activity against carbapenem-resistant Klebsiella pneumoniae (CRKP) isolates with outer membrane porin gene mutations. In: Poster Presented at: ID Week. 2019 Oct 2e6 [Washington, DC]. Langley GW, Cain R, Tyrell JM, et al. Profiling interactions of vaborbactam with metallo-b-Lactamases. Biorg Med Chem Lett. 2019;29:1981e1984. Saw HT, Webber MA, Mushtaq S, Woodford N, Piddock LJ, et al. Inactivation or inhibition of AcrABTolC increases resistance of carbapenemase-producing Enterobacteriaceae to carbapenems. J Antimicrob Chemother. 2016;71:1510 e1519. Biagi M, Wu T, Lee M, et al. Searching for the optimal treatment for metallo- and serine-b-lactamase producing Enterobacteriaceae: aztreonam in combination with ceftazidime-avibactam or meropenem-vaborbactam. Antimicrob Agents Chemother. 2019 [Epub ahead of print]. Kaushik A, Ammerman NC, Lee J, et al. In Vitro activity of the new blactamase inhibitors relebactam and vaborbactam in combination with blactams against Mycobacterium abscessus complex clinical isolates. Antimicrob Agents Chemother. 2019;63. E02623-18. Kaye KS, Bhowmick T, Metallidis S, et al. Effect of meropenemvaborbactam vs. piperacillintazobactam on clinical cure or

40.

41.

42.

43.

44.

improvement and microbial eradication in complicated urinary tract infections: the TANGO I randomized clinical trial. JAMA. 2018;319:788e799. Wunderink RG, GiamarellosBourbolis EJ, Rahav G, et al. Effect and safety of meropenemvaborbactam versus best-available therapy in patients with carbapenemresistant Enterobacteriaceae infections: the TANGO II randomized controlled trial. Infect Dis Ther. 2018;7:439e455. Bassetti M, Giacobbe DR, Patel N, et al. Efficacy and safety of meropenem-vaborbactam versus best-available therapy for the treatment of carbapenemresistant Enterobacteriaceae infections in patient without prior antimicrobial failure: a post hoc analysis. Adv Ther. 2019;36: 1771e1777. Shields R, McCreary E, Marini R, et al. Real-world experience with meropenem-vaborbactam (M/V) for treatment of carbapenem-resistant Enterobactericeae (CRE) Infections. In: Poster Presented at: ID Week. 2019 Oct 2e6 [Washington, DC]. Ackley R, Roshdy D, Isip J, et al. Recurrence of infection and emergence of drug resistance after treatment with meropenem/ vaborbactam compared to ceftazidime/avibactam in carbapenem-resistant Enterobacteriaceae infections. In: Poster Presented at: ID Week. 2019 Oct 2e6 [Washington, DC]. Clinical Trials.gov [Internet] Bethesda (MD): National Library of Medicine (Us). Identifier NCT03564158, A randomized, placebo- and positive-controlled, crossover study to evaluate the effect of meropenem-vaborbactam on the QT/QTc interval in Health volunteers. Available from: https:// clinicaltrials.gov/ct2/show/ NCT03564158.

Volume xxx Number xxx

B.R. Shoulders et al. 45. Athans V, Neuner EA, Hassouna H, et al. Meropenem-vaborbactam as salvage therapy for ceftazidimeavibactam-resistant Klebsiella pneumoniae bacteremia and abscess in a liver transplant recipient. Antimicrob Agents Chemother. 2019;63, e01555118. 46. Jorgensen SCJ, McDonald P, Mynatt RP, et al. Averting the postantibiotic era: successful use of meropenem-vaborbactam for carbapenem-resistant Serratia marcescens and Enterobacter aerogenes bacteremia in a hemodialysis patient. J Antimicrob Chemother. 2018;73:3529 e3531. 47. Kinn PM, Chen DJ, Gihring TM, et al. In vitro evaluation of meropenemvaborbactam against clinical CRE isolates at a tertiary care center with low KPC-mediated carbapenem resistance. Diagn Microbiol Infect Dis. 2019;93:258e260. 48. Bush K. Past and present perspective on b-lactamases. Antimicrob Agents Chemother. 2018;62(10), e01076-18. 49. Shaikh S, Fatima J, Shakil S, et al. Antibiotic resistance and extendedspectrum beta-lactamases: types, epidemiology, and treatment. Saudi J Biol Sci. 2015;22:90e101.

Address correspondence to: Bethany R. Shoulders, PharmD, BCCCP, Department of Pharmacotherapy and Translational Research, University of Florida College of Pharmacy, 1225 Center Dr, HPNP 2314A, Gainesville, FL 32610, USA. E-mail: [email protected]fl.edu

▪▪▪ xxxx

11